Abstract Migraine (MIG) is a prevalent (15-20%) and highly disabling disorder, with complex neurobiological underpinnings characterized by sensitization of the brainstem trigeminal sensory complex, leading to brainstem-mediated up-regulation of cortical and hypothalamic excitability. Our own pilot fMRI data found reduced habituation and amplified afferent input from the spinal trigeminal nucleus to cortical areas including posterior insula and hypothalamus. Reducing cortical/subcortical amplification and normalizing habituation may be an important therapeutic target. Multimodal approaches have shown improved clinical outcomes, and have been recommended in the recent Institute of Medicine report on pain. We propose that this is also the case for mind-body therapies. Mindfulness meditation (MM) has shown promise for migraine, and likely operates by top-down mechanisms, potentially reducing posterior insula and thalamic hyperexcitability. Furthermore, hyperexcitability may be mediated by the excitatory neurotransmitter glutamate, and recent MR spectroscopy (H-MRS) studies have found that increased glutamate in posterior insula is associated with hyperalgesia in chronic pain patients, while experienced meditators show reduced glutamate levels in the thalamus. Additionally, bottom-up therapies such as invasive and non-invasive auricular transcutaneous vagus nerve stimulation (tVNS) also reduce migraine frequency and disability. In tVNS, vagal afference relayed to nucleus tractus solitarii (NTS) in the medulla may modulate trigeminal sensory complex excitability and hyperexcitability in higher brain structures (i.e., a ?bottom-up? pathway), possibly by recruitment of serotonergic (raphe nuclei) and noradrenergic (locus coeruleus, LC) pathways, via NTS afference. Furthermore, the dorsal medullary vagal system operates in synchrony with respiration: NTS receiving inhibitory inputs from medullary ventral respiratory group (VRG) nuclei during inhalation, and facilitatory input during expiration. This is a critically- important feature of this circuitry, as it suggests that interventions utilizing this NTS pathway should be synchronized with respiration. Hence, our group developed Respiratory-gated Auricular Vagal Afferent Nerve Stimulation (RAVANS), that optimizes tVNS targeting of NTS by stimulating only during the expiratory phase. Thus, RAVANS tVNS incorporates bottom-up modulation of cortical/subcortical hyperexcitability in regions such as the posterior insula and thalamus, which are also targeted by MM-relevant circuits. In sum, we propose that MM training incorporating RAVANS tVNS will have a synergistic effect in reducing posterior insula, thalamic, and hypothalamic hyperexcitability in migraine.